Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine
Mesenchymal Stem Cells Reduce Colitis in Mice via Release of TSG6, Independently of Their Localization to the Intestine
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DOI：
10.1053/j.gastro.2015.03.013
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发表时间：
2015-07-01
期刊：
影响因子：
29.4
通讯作者：
Vetrano, Stefania
中科院分区：
文献类型：
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作者：
Sala, Emanuela;Genua, Marco;Vetrano, Stefania
背景与目的：间充质干细胞（MSC）是多能细胞，可以促进免疫调节细胞的扩增，并可能被开发用于治疗免疫疾病，包括炎症性肠病。据报道，MSC可以减少小鼠结肠炎;我们研究了MSC定位于肠道和产生旁分泌因子（包括肿瘤坏死因子诱导蛋白6（TSG 6））是否是这些效应所必需的。方法：从4 ~ 6周龄C57 BL/6、C57 BL/6-绿色荧光蛋白和Balb/c Tsg 6-/-雄性小鼠的骨髓中分离骨髓间充质干细胞（BM-MSCs）。通过随意施用葡聚糖硫酸钠10天来诱导结肠炎; 5天后，向小鼠腹膜内注射BM-MSC或盐水（对照）。在24、48、96和120小时后收集血液样品和肠组织;进行组织学和流式细胞术分析。研究结果：与对照组小鼠相比，注射BM-MSCs减少了小鼠的结肠炎，增加了体重，减少了肠道炎症标志物。然而，只有不到1%的MSC到达发炎的结肠。大部分骨髓间充质干细胞在腹腔内形成聚集体。聚集体含有巨噬细胞和B和T细胞，并产生免疫调节分子，包括FOXP 3、白细胞介素（IL）10、转化生长因子-β、II型趋化酶、趋化因子（C-C基序）配体22（CCL 22）、血红素加氧酶-1和TSG 6。与给予盐水的小鼠相比，给予BM-MSC的小鼠的血清具有增加的TSG 6水平。注射TSG 6可降低小鼠结肠炎的严重程度，沿着粘膜中CD 45+细胞、中性粒细胞和金属蛋白酶活性的数量，同时增加Foxp 3 CD 45+细胞的百分比。TSG 6注射还促进表达IL 10和诱导型一氧化氮合酶的调节性巨噬细胞的扩增，并降低干扰素-γ、IL 6和肿瘤坏死因子的血清水平。Tsg 6-/-MSC不能抑制结肠炎小鼠的粘膜炎症反应。结论：注射到患有结肠炎的小鼠中的BM-MSC不局限于肠道，而是在腹膜中形成聚集体，在那里它们产生免疫调节分子，包括TSG 6，从而减少肠道炎症。TSG 6足以减轻结肠炎小鼠的肠道炎症。
BACKGROUND & AIMS: Mesenchymal stem cells (MSCs) are pluripotent cells that can promote expansion of immune regulatory cells and might be developed for the treatment of immune disorders, including inflammatory bowel diseases. MSCs were reported to reduce colitis in mice; we investigated whether MSC localization to the intestine and production of paracrine factors, including tumor necrosis factor-induced protein 6 (TSG6), were required for these effects. METHODS: MSCs were isolated from bone marrow (BM-MSCs) of 4- to 6-week-old C57BL/6, C57BL/6-green fluorescent protein, or Balb/c Tsg6-/- male mice. Colitis was induced by ad libitum administration of dextran sulfate sodium for 10 days; after 5 days the mice were given intraperitoneal injections of BM-MSCs or saline (controls). Blood samples and intestinal tissues were collected 24, 48, 96, and 120 hours later; histologic and flow cytometry analyses were performed. RESULTS: Injection of BM-MSCs reduced colitis in mice, increasing body weight and reducing markers of intestinal inflammation, compared with control mice. However, fewer than 1% of MSCs reached the inflamed colon. Most of the BM-MSCs formed aggregates in the peritoneal cavity. The aggregates contained macrophages and B and T cells, and produced immune-regulatory molecules including FOXP3, interleukin (IL) 10, transforming growth factor-beta, arginase type II, chemokine (C-C motif) ligand 22 (CCL22), heme oxygenase-1, and TSG6. Serum from mice given BM-MSCs, compared with mice given saline, had increased levels of TSG6. Injection of TSG6 reduced the severity of colitis in mice, along with the numbers of CD45+ cells, neutrophils and metalloproteinase activity in the mucosa, while increasing the percentage of Foxp3CD45+ cells. TSG6 injection also promoted the expansion of regulatory macrophages that expressed IL10 and inducible nitric oxide synthase, and reduced serum levels of interferon-gamma, IL6, and tumor necrosis factor. Tsg6-/- MSCs did not suppress the mucosal inflammatory response in mice with colitis. CONCLUSIONS: BM-MSCs injected into mice with colitis do not localize to the intestine but instead form aggregates in the peritoneum where they produce immunoregulatory molecules, including TSG6, that reduce intestinal inflammation. TSG6 is sufficient to reduce intestinal inflammation in mice with colitis.